The primary goal of the proposed research is to develop a fast and generally applicable screening strategy for accelerating the identification and ranking of lead compounds in the drug discovery process. One of the major challenges faced by the current combinatorial library screening methodology is the ability to recognize and judge relative binding affinities of test compounds. We propose to use a general physicochemical property of ligand-receptor complexes as an experimental observable. An important objective will be to expand this concept in an automated high throughput 96 well plate format for screening large quantities of compounds from combinatorial chemical diversity libraries for preferential binding to therapeutic receptor targets. This screening strategy, based on a general physicochemical property of ligand-receptor complexes, will have important utility for the drug discovery process because of its speed and reproducibility. Moreover, it circumvents the requirement for inventing a new assay every time the therapeutic receptor target is substituted.